A large cohort study from the UK has reached the surprising conclusion that tricyclics are the safest class of antidepressants in elderly people. The cohort comprised 60,746 primary care patients aged 65 and over (mean age 75) with a new diagnosis of depression recorded between January 1 1996 and December 31 2007. The cohort was followed up until December 31 2008.

Overall, 89% of the cohort received at least one prescription for an antidepressant during the follow-up period (median duration of treatment was 12 months). The remaining 11% formed the control group.

Of the total number of prescriptions, 54.7% were for SSRIs, 31.6% were for tricyclics and 13.5% were for third generation drugs (mirtazapine and venlafaxine). Tricyclics were usually prescribed at low doses (70% were for ≤ 0.5 of the defined daily dose, which for amitriptyline is 75mg).¹

All classes of antidepressants were associated with significantly increased risks of all cause mortality, attempted suicide/self-harm, falls, fractures and upper GI bleeding, when compared with non-drug treatment.

SSRIs and third generation antidepressants were associated with significantly increased risks of stroke/TIA and epilepsy/seizures; SSRIs were also associated with increased risks of MI and hyponatraemia.

SSRIs were associated with the highest adjusted hazard ratios (HR) for falls, HR 1.66 (95% CI: 1.58-1.73) and hyponatraemia HR 1.52 (95% CI: 1.33-1.75). Third generation drugs were associated with the highest adjusted HRs for all cause mortality 1.66 (95% CI: 1.56-1.77), attempted suicide/self-harm 5.16 (95% CI: 3.90-6.83), stroke/TIA 1.37 (95% CI: 1.22-1.55), fracture 1.64 (95% CI: 1.46-1.84) and epilepsy/seizures 2.24 (95% CI: 1.60-3.15). Tricyclics did not have the highest adjusted HR for any of the outcomes.

Observational studies of drug treatment are hampered by confounding by indication. Both the decision whether or not to prescribe antidepressants and the choice of antidepressant drug will have been influenced by patient characteristics.

Thus, patients receiving non-drug treatment may have had milder depression or more comorbidity compared with those receiving antidepressants; and patients prescribed venlafaxine are likely to have had more severe or treatment resistant depression.

Elderly patients do not tolerate tricyclics as well as SSRIs (relative risk of withdrawal due to side effects 1.36 (95% CI: 1.09-1.70).2 For this reason, they are often prescribed at a lower dose than the recommended dose (≥125mg imipramine/amitriptyline equivalents).3 There is evidence that lower doses (75-100mg) are effective, but the minimum effective dose has not been established.4

It is surprising that the adjusted HR for MI was higher with SSRIs 1.15 (95% CI: 1.04-1.27) than with tricyclics 1.09 (95% CI: 0.96-1.23). Tricyclics are thought to be pro-arrhythmic and a recent prospective cohort study found the use of tricyclics was associated with an increased risk of cardiovascular disease HR 1.35 (95% CI: 1.03-1.77).5

Perhaps the most striking result from this study is that almost 90% of the patients were given antidepressants. For elderly patients with mild to moderate depression, the risks of antidepressant medication are likely to outweigh the benefits, and a psychosocial intervention may well be preferable.

If we are to prescribe, I do not think there is sufficient evidence to justify prescribing very low dose tricyclics (

Dr Phillip Bland